The overall aim of this application is to better understand the role of endogenous Glucagon-Like Peptide-1(GLP-1) signaling, primarily in the fasting state, to influence ?-cell and ?-cell function both during the fasting state and in response to subsequent meal challenges. This has been an ignored aspect of GLP-1 physiology, given its primarily post-prandial effects. However, therapeutic agents that harness the GLP-1 pathway lower both fasting and postprandial glucose concentrations. In addition, a non-synonymous Single Nucleotide Polymorphism in the GLP-1 receptor, rs3765467, previously shown by us to enhance response to hyperglycemia and to GLP-1, lowers fasting glucose and protects from type 2 diabetes (T2DM). GLP-1 arises by post-translational processing of proglucagon by a specific prohormone convertase enzyme (PC-1/3). There is evidence that this enzyme can be expressed within the islet enabling local production of GLP-1. This may function in a paracrine fashion to augment glucose-stimulated insulin secretion and glucose mediated suppression of glucagon. Expression of PC-1/3 and GLP-1 is increased in T2DM and also by exposure to hyperglycemia and free fatty acids. An explanation of these observations is that GLP-1 may help islet adaptation to metabolic stressors at least early in the course of T2DM. Intriguingly, our preliminary data shows that the effect of antagonizing fasting endogenous GLP-1 secretion differs between people with and without T2DM. Another aspect of ?-cell to ?-cell communication is that intra-islet glucagon concentrations can act as stimulus to insulin secretion, signaling partially through the GLP-1 receptor. The importance of this in normal physiology and in T2DM is unknown. The proposed experiments will elucidate how rs3765467 alters islet function in the presence and absence of GLP-1 receptor blockade. In addition, we will examine the role of endogenous GLP-1 secretion in T2DM and compare responses to metabolic stress. The experimental conditions will also enable us to examine the role of GLP-1 signaling in the insulin secretory response to glucagon. Successful completion of these experiments will clarify the role of endogenous GLP-1 in vivo.